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Prevention of neuronal apoptosis has been introduced as a new therapeutic strategy for neurodegenerative disorders. We have previously reported anti-apoptotic effects of transforming growth factor-β1 (TGF-β1), a multifunctional cytokine, in models of cerebral ischemia and in cultured neurons and recently focused on the mechanisms underlying the anti-apoptotic effect of TGF-β1. The anti-apoptotic transcriptional factor nuclear factor kappa B (NF-κB) shows high impact in the cell survival function of multiple cytokines and growth factors. The present study explored whether NF-κβ is a target of TGF-β1 and which signaling pathways involved in the activation of NF-κβ are triggered by TGF-β1. We demonstrated that TGF-β1 increased the transcriptional activity of NF-κβ in cultured hippocampal neurons in a time- and concentration-dependent manner. Furthermore, TGF-β1 induced translocation of p65/NF-κβ to the nucleus and enhanced NF-κβ transcriptional activity in the presence of apoptotic stimuli. TGF-β1-mediated NF-κβ activation was blocked by wortmannin and U0126, indicating the involvement of both phosphatidylinositol-3-OH kinase (PI3k)/Akt and mitogen-activated protein kinase (MAPK)/extracellular-signal regulated kinase (Erk)1,2 pathways in the action of TGF-β1. TGF-β1 produced a concomitant increase in the phosphorylations of Iκβ kinase (IKKα/β) and Iκβα with a subsequent degradation of Iκβα. Interestingly, the increased phosphorylation of IKKα/β and Iκβα was abrogated by wortmannin, but not by U0126, suggesting that PI3k/Akt and MAPK/Erk1,2 pathways triggered by TGF-β1 regulated the activation of NF-κβ through different mechanisms. Of note, wortmannin and U0126, as well as κβ-decoy DNA, abolished the anti-apoptotic effect of TGF-β1, corroborating the notion that both PI3k/Akt and MAPK/Erk1,2 pathways, and NF-κβ activity are necessary for the anti-apoptotic activity of TGF-β1. [Copyright &y& Elsevier]

The role of the common neurotrophin receptor p75 (p75NTR) in neuronal survival and cell death remains controversial. On the one hand, p75NTR provides a positive modulatory influence on nerve growth factor (NGF) signaling through the high affinity neurotrophin receptor TrkA, and hence increases NGF survival signaling. However, p75NTR may also signal independently of TrkA, causing cell death or cell survival, depending on the cell type and stage of development. Here we demonstrate that TrkA is expressed in primary cultures of hippocampal neurons and is activated by NGF within 10 min of exposure. In primary hippocampal cultures neuroprotection by NGF against glutamate toxicity was mediated by NF-κB and accompanied by an increased expression of neuroprotective NF-κB target genes Bcl-2 and Bcl-xl. In mouse hippocampal cells lacking p75NTR (p75NTR−/−) activation of TrkA by NGF was not detectable. Moreover, neuroprotection by NGF against glutamate toxicity was abolished in p75NTR−/− neurons, and the expression of bcl-2 and bcl-xl was markedly reduced as compared to wildtype cells. NGF increased TrkA phosphorylation in hippocampal neurons and provided protection that required phosphoinositol-3-phosphate (PI3)-kinase activity and Akt phosphorylation, whereas the mitogen-activated protein kinases (MAPK), extracellular-regulated kinases (Erk) 1/2, were not involved. P75NTR signaling independent of TrkA, such as increased neutral sphingomyelinase (NSMase) activity causing enhanced levels of ceramide, were not detected after exposure of hippocampal neurons to NGF. Interestingly, inhibition of sphingosine-kinase blocked the neuroprotective effect of NGF, suggesting that sphingosine-1-phosphate was also involved in NGF-mediated survival in our cultured hippocampal neurons. Overall, our results indicate an essential role for p75NTR in supporting NGF-triggered TrkA signaling pathways mediating neuronal survival in hippocampal neurons. [Copyright &y& Elsevier]

Background: The administration of intravenous fluids includes various indications, e.g., fluid replacement, nutritional therapy or as a solvent for drugs and is a common routine in the intensive care unit (ICU); however, overuse of intravenous fluids can lead to fluid overload, which can be associated with a poorer outcome in critically ill patients. Objective: The aim of this survey was to find out the current status of the use and management of intravenous fluids as well as the interprofessional cooperation involving clinical pharmacists on German ICUs. Methods: An online survey with 33 questions was developed. The answers of 62 participants from the Scientific Working Group on Intensive Care Medicine of the German Society for Anesthesiology and Intensive Care Medicine were evaluated. Results: Fluid overload occurs "frequently" in 62.9% (39/62) and "very frequently" in 9.7% (6/62) of the ICUs of respondents. An established standard for an infusion management system is unknown to 71.0% (44/62) of participants and 45.2% of the respondents stated that they did not have a patient data management system. In addition, the participants indicated how they define fluid overload. This was defined by the presence of edema by 50.9% (28/55) and by positive fluid balance by 30.9% (17/55). According to the participants septic patients (38/60; 63.3%) and cardiological/cardiac surgical patients (26/60; 43.3%) are most susceptible to the occurrence of fluid overload. Interprofessional collaboration among intensive care physicians, critical care nurses, and clinical pharmacists to optimize fluid therapy was described as "relevant" by 38.7% (24/62) and "very relevant" by 45.2% (28/62). Participants with clinical pharmacists on the wards (24/62; 38.7%) answered this question more often as "very relevant" with 62.5% (15/24). Conclusion: Fluid overload is a frequent and relevant problem in German intensive care units. Yet there are few established standards in this area. There is also a lack of validated diagnostic parameters and a clear definition of fluid overload. These are required to ensure appropriate and effective treatment that is tailored to the patient and adapted to the respective situation. Intravenous fluids should be considered as drugs that may exert side effects or can be overdosed with severe adverse consequences for the patients. One approach to optimize fluid therapy could be achieved by a fluid stewardship corresponding to comparable established procedures of the antibiotic stewardship. In particular, fluid stewardship will contribute to drug safety of intravenous fluids profiting from joined expertise in a setting of interprofessional collaboration. An important principle of fluid stewardship is to consider intravenous fluids in the same way as medication in terms of their importance. Furthermore, more in-depth studies are needed to investigate the effects of interprofessional fluid stewardship in a prospective and controlled manner. [ABSTRACT FROM AUTHOR]

Solid tumors often have an inadequate blood supply, which results in large regions that are subjected to hypoxic or anoxic stress. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates much of the transcriptional response of cells to hypoxia. Activating transcription factor 3 (ATF3) is another transcription factor that responds to a variety of stresses and is often upregulated in cancer. We investigated the regulation of ATF3 by oxygen deprivation. ATF3 induction occurred most robustly under anoxia, is common, and it is not dependent on presence of HIF-1 or p53, but is sensitive to the inhibition of c-Jun NH2-terminal kinase activation and the antioxidant N-acetylcystein. ATF3 could also be induced by desferrioxamine but not by the mitochondrial poison cyanide or the nonspecific 2-oxoglutarate dioxygenase inhibitor dimethyloxalylglycine. We also show that anoxic ATF3 mRNA is more stable than normoxic mRNA providing a mechanism for this induction. Thus, this study demonstrates that the regulation of ATF3 under anoxia is independent of 2-oxoglutarate dioxygenase, HIF-1 and p53, presumably involving multiple regulatory pathways.Oncogene (2007) 26, 284–289. doi:10.1038/sj.onc.1209781; published online 17 July 2006 [ABSTRACT FROM AUTHOR]

We have previously shown that nerve growth factor (NGF)-induced activation of nuclear factor-κB increased neuronal expression of Bcl-xL, an anti-apoptotic Bcl-2 family protein. In the present study we determined the role of the p75 neurotrophin receptor in constitutive and NGF-induced survival signalling. Treatment of rat pheochromocytoma (PC12) cells with a blocking anti-rat p75 antibody or inhibition of p75 expression by antisense oligonucleotides reduced constitutive and NGF-induced bcl-xL expression. Treatment with the blocking anti-p75 antibody also inhibited NGF-induced activation of the survival kinase Akt. Inhibition of phosphatidylinositol-3-kinase (PI3 kinase) activity or overexpression of a dominant-negative mutant of Akt kinase inhibited NGF-induced nuclear factor-κB activation. Activation of Akt kinase by NGF was also observed in PC12nnr5 cells and cultured rat hippocampal neurones which both lack significant TrkA expression. Treatment of hippocampal neurones with the blocking anti-p75 antibody inhibited constitutive and NGF-induced Bcl-xL expression, activation of Akt, and blocked the protective effect of NGF against excitotoxic and apoptotic injury. Our data suggest that the p75 neurotrophin receptor mediates constitutive and NGF-induced survival signalling in PC12 cells and hippocampal neurones, and that these effects are mediated via the PI3-kinase pathway. [ABSTRACT FROM AUTHOR]

Recent studies indicate that the Tg2576 transgenic mouse model of Alzheimer's disease [tg(hAPP)] demonstrates disturbances in plasma glucose and neuroendocrine function reminiscent of Alzheimer's disease (AD). Alterations in any one of these systems can have a profound effect on hepatic cytochrome P450 (CYP) expression. Additionally, the recent discovery that amyloid beta 1–42 can induce the expression of CYP reductase in neuronal cultures further suggests that hepatic CYP-related metabolism may be affected by the expression of mutant human amyloid precursor protein in these tg(hAPP) mice. Therefore, the current study was conducted to investigate the activity and protein content of several CYP isoforms in the livers and kidneys of aged (20-month-old) tg(hAPP) mice. tg(hAPP) mice exhibit significant elevations in hepatic CYP2B, CYP2E1-, CYP3A- and CYP4A-associated activities and CYP4A immunoreactive protein compared with wild-type. In contrast to the liver, a significant depression in renal CYP2E1- and CYP4A-associated activities were demonstrated in tg(hAPP) mice. The presence of the mutant hAPP protein was detected in the brain, kidney and livers of tg(hAPP) mice. [ABSTRACT FROM AUTHOR]

Background: This overview focuses on the aspects of the pharmacotherapy of Parkinson's disease, which is one of the most common disorders of the nervous system. This article presents the complexity of the pharmacotherapy of geriatric patients with neurological diseases. Objectives: Information about the potential risk factors and aspects of drug safety in the pharmacotherapy of Parkinson's disease. Materials and methods: Selective literature search using PubMed and the scientific-clinical experience of the authors. Results: Patients with Parkinson's disease are usually geriatric patients with concomitant diseases. As a result they are often treated with comedication which leads to a complex medication regime with more than five drugs. Such polypharmacy increases the risk of adverse drug events due to the rising number of possible interactions and contraindications. To control this risk and maintain a safe therapy, certain measures should be considered. This implies additional need for educational work in order to create awareness regarding potential adverse drug events. In certain cases of diagnosed comorbidities or relevant drug prescriptions in the medication regime, follow-up examinations should be conducted. Conclusion: Specific parameters of Parkinson's disease, the health-related quality of life of affected patients and the quality of pharmacotherapeutic drug safety can be improved by targeted monitoring of the medication regime. As a result, the overall drug safety can be increased. [ABSTRACT FROM AUTHOR]

Impaired regulation of mitochondrial dynamics, which shifts the balance towards fission, is associated with neuronal death in age-related neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. A role for mitochondrial dynamics in acute brain injury, however, has not been elucidated to date. Here, we investigated the role of dynamin-related protein 1 (Drp1), one of the key regulators of mitochondrial fission, in neuronal cell death induced by glutamate toxicity or oxygen-glucose deprivation (OGD) in vitro, and after ischemic brain damage in vivo. Drp1 siRNA and small molecule inhibitors of Drp1 prevented mitochondrial fission, loss of mitochondrial membrane potential (MMP), and cell death induced by glutamate or tBid overexpression in immortalized hippocampal HT-22 neuronal cells. Further, Drp1 inhibitors protected primary neurons against glutamate excitotoxicity and OGD, and reduced the infarct volume in a mouse model of transient focal ischemia. Our data indicate that Drp1 translocation and associated mitochondrial fission are key features preceding the loss of MMP and neuronal cell death. Thus, inhibition of Drp1 is proposed as an efficient strategy of neuroprotection against glutamate toxicity and OGD in vitro and ischemic brain damage in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Detection of neuronal cell death is a standard requirement in cell culture models of neurodegenerative diseases. Although plenty of viability assays are available for in vitro applications, most of these are endpoint measurements providing only little information on the kinetics of cell death. Here, we validated the xCELLigence system based on impedance measurement for real-time detection of cell death in a neuronal cell line of immortalized hippocampal neurons (HT-22 cells), neuronal progenitor cells (NPC) and differentiated primary cortical neurons. We found a good correlation between impedance measurements and endpoint viability assays in HT-22 cells and NPC, for detecting proliferation, cell death kinetics and also neuroprotective effects of pharmacological inhibitors of apoptosis. In primary neurons we could not detect dendritic outgrowth during differentiation of the cells. Cell death in primary neurons was detectable by the xCELLigence system, however, the changes in the cell index on the basis of impedance measurements depended to a great extent on the severity of the insult. Cell death induced by ionomycin, e.g. shows as a fast paced process involving a strong cellular disintegration, which allows for impedance-based detection. Cell death accompanied by less pronounced morphological changes like glutamate induced cell death, however, is not well accessible by this approach. In conclusion, our data show that impedance measurement is a convenient and reliable method for the detection of proliferation and kinetics of cell death in neuronal cell lines, whereas this method is less suitable for the assessment of neuronal differentiation and viability of primary neurons. [Copyright &y& Elsevier]

Glutamate toxicity involves increases in intracellular calcium levels and enhanced formation of reactive oxygen species (ROS) causing neuronal dysfunction and death in acute and chronic neurodegenerative disorders. The molecular mechanisms mediating glutamate-induced ROS formation are, however, still poorly defined. Using a model system that lacks glutamate-operated calcium channels, we demonstrate that glutamate-induced acceleration of ROS levels occurs in two steps and is initiated by lipoxygenases (LOXs) and then significantly accelerated through Bid-dependent mitochondrial damage. The Bid-mediated secondary boost of ROS formation downstream of LOX activity further involves mitochondrial fragmentation and release of mitochondrial apoptosis-inducing factor (AIF) to the nucleus. These data imply that the activation of Bid is an essential step in amplifying glutamate-induced formation of lipid peroxides to irreversible mitochondrial damage associated with further enhanced free radical formation and AIF-dependent execution of cell death. [ABSTRACT FROM AUTHOR]

Apoptosis-inducing factor (AIF) has important supportive as well as potentially lethal roles in neurons. Under normal physiological conditions, AIF is a vital redox-active mitochondrial enzyme, whereas in pathological situations, it translocates from mitochondria to the nuclei of injured neurons and mediates apoptotic chromatin condensation and cell death. In this study, we reveal the existence of a brain-specific isoform of AIF, AIF2, whose expression increases as neuronal precursor cells differentiate. AIF2 arises from the utilization of the alternative exon 2b, yet uses the same remaining 15 exons as the ubiquitous AIF1 isoform. AIF1 and AIF2 are similarly imported to mitochondria in which they anchor to the inner membrane facing the intermembrane space. However, the mitochondrial inner membrane sorting signal encoded in the exon 2b of AIF2 is more hydrophobic than that of AIF1, indicating a stronger membrane anchorage of AIF2 than AIF1. AIF2 is more difficult to be desorbed from mitochondria than AIF1 on exposure to non-ionic detergents or basic pH. Furthermore, AIF2 dimerizes with AIF1, thereby preventing its release from mitochondria. Conversely, it is conceivable that a neuron-specific AIF isoform, AIF2, may have been ‘designed’ to be retained in mitochondria and to minimize its potential neurotoxic activity. [ABSTRACT FROM AUTHOR]

Abstract: Excitotoxicity is one of the main features responsible for neuronal cell death after acute brain injury and in several neurodegenerative disorders, for which only few therapeutic options are currently available. In this work, RNA interference was employed to identify and validate a potential target for successful treatment of excitotoxic brain injury, the transcription factor c-Jun. The nuclear translocation of c-Jun and its upregulation are early events following glutamate-induced excitotoxic damage in primary neuronal cultures. We present evidence for the efficient knockdown of this transcription factor using a non-viral vector consisting of cationic liposomes associated to transferrin (Tf-lipoplexes). Tf-lipoplexes were able to deliver anti-c-Jun siRNAs to neuronal cells in culture, resulting in efficient silencing of c-Jun mRNA and protein and in a significant decrease of cell death following glutamate-induced damage or oxygen–glucose deprivation. This formulation also leads to a significant c-Jun knockdown in the mouse hippocampus in vivo, resulting in the attenuation of both neuronal death and inflammation following kainic acid-mediated lesion of this region. Furthermore, a strong reduction of seizure activity and cytokine production was observed in animals treated with anti-c-Jun siRNAs. These findings demonstrate the efficient delivery of therapeutic siRNAs to the brain by Tf-lipoplexes and validate c-Jun as a promising therapeutic target in neurodegenerative disorders involving excitotoxic lesions. [Copyright &y& Elsevier]

Abstract: Although RNAi-based gene silencing holds a great potential for treatment of neurological disorders, its application to the CNS has been restricted by low levels of tissue distribution and cellular uptake. In this work we report that cationic lipid-based vectors can enhance siRNA delivery to neurons both in vitro and in vivo. DOTAP:Chol liposomes associated with transferrin (Tf) and complexed with siRNAs (Tf-lipoplexes) were delivered to primary cultures of luciferase-expressing cortical neurons. Confocal microscopy studies revealed efficient cellular uptake of Cy3-labelled siRNAs after Tf-lipoplex delivery, which was reduced but not completely inhibited by blocking the Tf-receptor with excess Tf. Gene silencing was also evaluated after delivery of anti-luciferase or anti-c-Jun siRNAs. Our results demonstrate that Tf-lipoplexes achieve up to 50% luciferase and c-Jun knockdown, 48 h after transfection, without significant cytotoxicity. Similar results were observed in vivo, where a 40% reduction of luciferase activity was found in the striatum of luciferase mice. In addition, fluorescence microscopy studies showed extensive local distribution and internalization of Tf-lipoplex-associated Cy3-siRNAs without tissue toxicity. Overall, our results demonstrate that Tf-lipoplexes can mediate efficient gene silencing in neuronal cells, both in vitro an in vivo, which may prove useful in therapeutic approaches to neuronal protection and repair. [Copyright &y& Elsevier]

Mitochondrial dysfunction and release of pro-apoptotic factors such as cytochrome c or apoptosis-inducing factor (AIF) from mitochondria are key features of neuronal cell death. The precise mechanisms of how these proteins are released from mitochondria and their particular role in neuronal cell death signaling are however largely unknown. Here, we demonstrate by fluorescence video microscopy that 8–10 h after induction of glutamate toxicity, AIF rapidly translocates from mitochondria to the nucleus and induces nuclear fragmentation and cell death within only a few minutes. This markedly fast translocation of AIF to the nucleus is preceded by increasing translocation of the pro-apoptotic bcl-2 family member Bid (BH3-interacting domain death agonist) to mitochondria, perinuclear accumulation of Bid-loaded mitochondria, and loss of mitochondrial membrane integrity. A small molecule Bid inhibitor preserved mitochondrial membrane potential, prevented nuclear translocation of AIF, and abrogated glutamate-induced neuronal cell death, as shown by experiments using Bid small interfering RNA (siRNA). Cell death induced by truncated Bid was inhibited by AIF siRNA, indicating that caspase-independent AIF signaling is the main pathway through which Bid mediates cell death. This was further supported by experiments showing that although caspase-3 was activated, specific caspase-3 inhibition did not protect neuronal cells against glutamate toxicity. In conclusion, Bid-mediated mitochondrial release of AIF followed by rapid nuclear translocation is a major mechanism of glutamate-induced neuronal death.Cell Death and Differentiation (2008) 15, 1553–1563; doi:10.1038/cdd.2008.78; published online 6 June 2008 [ABSTRACT FROM AUTHOR]

Acute and chronic neurodegeneration, for example, following brain injury or Alzheimer's disease, is characterized by programmed death of neuronal cells. The present study addresses the role and interaction of p53- and NF-κB-dependent mechanisms in delayed neurodegeneration following traumatic brain injury (TBI). After experimental TBI in mice p53 rapidly accumulated in the injured brain tissue and translocated to the nucleus of damaged neurons, whereas NF-κB transcriptional activity simultaneously declined. Post-traumatic neurodegeneration correlated with the increase in p53 levels and was significantly reduced by the selective p53 inhibitor pifithrin-α (PFT). Strikingly, this protective effect was observed even when PFT treatment was delayed up to 6 h after trauma. Inhibition of p53 activity resulted in the concomitant increase in NF-κB transcriptional activity and upregulation of NF-κB-target proteins, for example X-chromosomal-linked inhibitor of apoptosis (XIAP). It is interesting to note that inhibition of XIAP abolished the neuroprotective effects of PFT in cultured neurons exposed to camptothecin, glutamate, or oxygen glucose deprivation. In conclusion, delayed neuronal cell death after brain trauma is mediated by p53-dependent mechanisms that involve inhibition of NF-κB transcriptional activity. Hence, p53 inhibition provides a promising approach for the treatment of acute brain injury, since it blocks apoptotic pathways and concomitantly triggers survival signaling with a therapeutic window relevant for clinical applications.Cell Death and Differentiation (2007) 14, 1529–1541; doi:10.1038/sj.cdd.4402159; published online 27 April 2007 [ABSTRACT FROM AUTHOR]

Nine-day-old harlequin (Hq) mice carrying the hypomorphic apoptosis-inducing factor (AIF)Hq mutation expressed 60% less AIF, 18% less respiratory chain complex I and 30% less catalase than their wild-type (Wt) littermates. Compared with Wt, the infarct volume after hypoxia-ischemia (HI) was reduced by 53 and 43% in male (YXHq) and female (XHqXHq) mice, respectively (P<0.001). The Hq mutation did not inhibit HI-induced mitochondrial release of cytochrome c or activation of calpain and caspase-3. The broad-spectrum caspase inhibitor quinoline-Val-Asp(OMe)-CH2-PH (Q-VD-OPh) decreased the activation of all detectable caspases after HI, both in Wt and Hq mice. Q-VD-OPh reduced the infarct volume equally in Hq and in Wt mice, and the combination of Hq mutation and Q-VD-OPh treatment showed an additive neuroprotective effect. Oxidative stress leading to nitrosylation and lipid peroxidation was more pronounced in ischemic brain areas from Hq than Wt mice. The antioxidant edaravone decreased oxidative stress in damaged brains, more pronounced in the Hq mice, and further reduced brain injury in Hq but not in Wt mice. Thus, two distinct strategies can enhance the neuroprotection conferred by the Hq mutation, antioxidants, presumably compensating for a defect in AIF-dependent redox detoxification, and caspase inhibitors, presumably interrupting a parallel pathway leading to cellular demise.Cell Death and Differentiation (2007) 14, 775–784. doi:10.1038/sj.cdd.4402053; published online 13 October 2006 [ABSTRACT FROM AUTHOR]

The article presents an abstract of the article "17β-Estradiol and 2-OH-Estradiol Reduce Brain Injury Caused by Cerebral Ischemia in Mice and Protect Cultured Chick Neurons From Oxidative Damage," by A. Ravati, V. Junker, C. Culmsee, B. Ahlemeyer, D. Otto, J.C. Krieg, H. Vedder and J. Krieglstein. The authors examined the effect of the estrogen derivatives 17β-estradiol and 2-OH-estradiol on ischemic brain damage in male mice.

N-cyclohexyl-N-[2-(3,5-dimethyl-pyrazol-1-yl)]-6-methyl-4-pyrimidinamine (CyPPA), a positive pharmacological activator of small conductance calcium-activated potassium channels, has been shown to antagonize lipopolysaccharide(LPS)-induced cytokine-expression in microglial cell cultures and, thus, has potential to treat neuroinflammation. Here, we aimed to investigate the effects of CyPPA on the brain during severe LPS-induced (2.5 mg/kg, intraperitoneal) systemic inflammation in mice. Pretreatment with CyPPA (15 mg/kg) injected 24 h prior and simultaneously with LPS-stimulation did not affect LPS-induced microglial activation, illness responses (depressed activity, anorexia and fever) and expression profiles of inflammatory mediators in the hypothalamus and in the periphery. However, CyPPA alone induced a rise in body core temperature that was accompanied by increased locomotor activity, decreased mRNA-expression of suppressor of cytokine signaling 3, increased expression of nuclear factor interleukin 6 and inhibitor of kappa B alpha in the hypothalamus while circulating cytokines were unaltered. Moreover, nuclear factor kappa B-activation was reduced in cortical neurons as revealed by western blot analyses potentially linked to some previously described neuroprotective capacities of CyPPA. Interestingly, we found reduced levels of adenosine, but a tendency of enhanced ATP and ADP in the liver of CyPPA-treated mice as measured by HPLC suggesting enhanced metabolism by CyPPA. Overall, while CyPPA might be suitable to modulate and treat some neuroinflammatory processes, the observed effects on metabolism, body core temperature and locomotor activity represent potential important side effects that should be taken into account. [ABSTRACT FROM AUTHOR]